Pharmacogenomics
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Aim: Identify variants in RYR1, CACNA1S and STAC3, and predict malignant hyperthermia (MH) pathogenicity using Bayesian statistics in individuals clinically treated as MH susceptible (MHS). Materials & methods: Whole exome sequencing including RYR1, CACNA1S and STAC3 performed on 64 subjects with: MHS; suspected MH event or first-degree relative; and MH negative. Variant pathogenicity was estimated using in silico analysis, allele frequency and prior data to calculate Bayesian posterior probabilities. ⋯ Met187Thr has uncertain significance. Nearly a third of MHS subjects had only benign variants. Conclusion: Bayesian method provides new approach to predict MH pathogenicity of genetic variants.
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Aim: The appropriate use and integration of pharmacogenetic (PGx) testing will pivot on provider preparation and training. Pharmacists have been recognized as one of the key providers in the delivery of PGx testing and as such, professional organizations have recommended inclusion of PGx content in pharmacy curricula. ⋯ Results: A total of 70 core curriculum courses were identified. 55 (42%) pharmacy schools included at least one PGx course as part of the core curriculum, and ten (8%) schools that offered a PGx course elective. Conclusion: While many pharmacy schools have responded to the accreditation standards to include PGx, less than half of the schools have developed a standalone course.
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Clinical Trial
Drug-gene and drug-drug interactions associated with tramadol and codeine therapy in the INGENIOUS trial.
Background: Tramadol and codeine are metabolized by CYP2D6 and are subject to drug-gene and drug-drug interactions. Methods: This interim analysis examined prescribing behavior and efficacy in 102 individuals prescribed tramadol or codeine while receiving pharmaco-genotyping as part of the INGENIOUS trial (NCT02297126). ⋯ After adjusting the CYP2D6 activity score for drug-drug interactions, uncontrolled pain was reported more frequently in individuals with reduced CYP2D6 activity (odds ratio: 0.50; 95% CI: 0.25-0.94). Conclusion: Phenoconversion for drug-drug and drug-gene interactions is an important consideration in pharmacogenomic implementation; drug-drug interactions may obscure the potential benefits of genotyping.
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Carbamazepine (CBZ) is a common cause of life-threatening cutaneous adverse drug reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Previous studies have reported a strong association between the HLA genotype and CBZ-induced SJS/TEN. We investigated the association between the HLA genotype and CBZ-induced SJS/TEN in Javanese and Sundanese patients in Indonesia. ⋯ Interestingly, we also observed the presence of the HLA-B*15:21 allele. HLA-B*15:02 and HLA-B*15:21 are members of the HLA-B75 serotype, for which a greater frequency was observed in CBZ-induced SJS/TEN (vs tolerant control [p = 0.0078; OR: 12; 95% CI: 1.90-75.72] and vs normal control [p = 0.0018; OR: 8.56; 95% CI: 1.83-40]). Our findings suggest that screening for the HLA-B75 serotype can predict the risk of CBZ-induced SJS/TEN more accurately than screening for a specific allele.
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Beside drug metabolizing enzymes alsogenetically variable membrane transporters may substantially contribute to the interindividual variability in pharmacokinetics and efficacy of opioids and other analgesics. The organic cation transporter OCT1 is strongly expressed in the sinusoidal membrane of the human liver. It may affect hepatic uptake and thus limit metabolic rates. ⋯ Genetic polymorphisms lead to substantially reduced OCT1 activity in up to 9% of the Europeans and the white Americans. This review summarize the data on the effect of OCT1 polymorphisms on pharmacokinetics and efficacy of opioids like morphine, codeine, and tramadol and of anti-migraine drugs. It discuss currently possible applications and perspectives for establishing OCT1 pharmacogenetics as a useful tool in personalized pain management.